Peptide and peptide mimetic conjugates with integrin-inhibitor properties

ABSTRACT

The invention relates to compounds of formula (1) I-Q-X 1 , wherein B is bioactive cell adhesive mediating molecule. Q is absent or is an inorganic spacer molecule and X 1  is an anchor molecule, selected from the group Lys.(CO—CH —(CH 2 ) n —PO 3 H 2 ) 2 (I)-Lys[-Lys-(CO—CH 2 —(CH 2 ) a —PO 3 H 2 ) 2 ] 2 (ii) or -Lys-(Lys[-Lys-(CO—CH 2 —(CH 2 ) n —PO 3 H 2 ] 2  (iii), and n independently represents 0, 1, 2 or 3, wherein a free amino group of group B is linked in peptide form to a free carboxyl group of the spacer molecule Q or of the anchor molecule X 1  or a free amino group of the radical Q is linked in peptide form to a free carboxyl group of the radical X 1 . The invention also relates to the salts thereof. The inventive compounds can be used as integrin inhibitors for the treatment of illnesses, deficiencies, inflammations caused by implants and osteolytic illnesses such as osteoporosis, thrombosis, cardiac infarction and arteriosclerosis, in addition to the acceleration and strengthening of the integration process of implants or the biocompatible surface in tissue.

[0001] The invention relates to compounds of the formula I

B-Q-X₁  I

[0002] in which

[0003] B is a bioactive, cell adhesion-mediating molecule

[0004] Q is absent or is an organic spacer molecule and

[0005] X₁ is an anchor molecule selected from the group

[0006] -Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂  (i)

[0007] -Lys-[Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂  (ii) or

[0008] -Lys-(Lys[-Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂)₂  (iii),

[0009] and n, in each case independently of one another, is 0, 1, 2 or 3and where a free amino group of the group B and a free carboxyl group ofthe spacer molecule Q or of the anchor molecule X₁ or a free amino groupof the radical Q and a free carboxyl group of the radical X₁ are linkedto one another like peptides, and their salts.

[0010] Similar compounds are disclosed in DE 19932796, DE 19755800 andDE 19831710.

[0011] The invention was based on the object of finding novel compoundshaving valuable properties, in particular those which can be used forthe production of medicaments.

[0012] It has been found that the compounds of the formula I and theirsalts have very valuable pharmacological properties, together with goodtolerability. They act especially as integrin inhibitors, inhibiting, inparticular, the interactions of the α_(v)β₃ or α_(v)β₅ integrinreceptors with ligands, e.g. the binding of fibrinogen to the β₃integrin receptor. The compounds show particular activity in the case ofthe integrins β_(v)β₃, α_(v)β₅,

[0013] This action can be demonstrated, for example, according to themethod which is described by J. W. Smith et al. in J. Biol. Chem. 265,12267-12271 (1990).

[0014] The dependence of the development of angiogenesis on theinteraction between vascular integrins and extra-cellular matrixproteins is described by P. C. Brooks, R. A. Clark and D. A. Cheresh inScience 264, 569-71 (1994).

[0015] The possibility of inhibiting this interaction and therebyinducing apoptosis (programmed cell death) of angiogenic vascular cellsby means of a cyclic peptide is described by P. C. Brooks, A. M.Montgomery, M. Rosenfeld, R. A. Reisfeld, T.-Hu, G. Klier and D. A.Cheresh in Cell 79, 1157-64 (1994).

[0016] Compounds of the formula I which block the interaction ofintegrin receptors and ligands, e.g. of fibrinogen to the fibrinogenreceptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists,the spread of tumour cells by metastasis. This is confirmed by thefollowing observations:

[0017] the spread of tumour cells from a local tumour into the vascularsystem takes place through the formation of microaggregates(microthrombi) by interaction of the tumour cells with blood platelets.The tumour cells are screened by the protection in the microaggregateand are not recognized by the cells of the immune system. Themicroaggregates can attach to vessel walls, owing to which furtherpenetration of tumour cells into the tissue is facilitated.

[0018] Since the formation of the microthrombi is mediated by fibrinogenbinding to the fibrinogen receptors on activated blood platelets, theGPIIa/IIIb antagonists can be regarded as effective metastasisinhibitors.

[0019] The phosphonate radical serves to bind the peptides ionically oradsorptively to biocompatible surfaces of, for example, implants whichcontain the oxides, e.g. metal surfaces (e.g. titanium or titaniumalloys such as TiAl₆V₄) or cation-containing surfaces, e.g. on amorphousor sintered calcium phosphate (e.g. hydroxy-apatite, bones, teeth) orcalcium phosphate cements (e.g. Biocement D).

[0020] The invention therefore relates in particular to the compounds ofthe formula I for ionic or adsorptive binding via the functional groupof the radical X₁ to biocompatible surfaces.

[0021] The peptides according to the invention now make possible thebiofunctionalization of biomaterials, in particular implants for humanand animal organs, by means of coating thereof, mainly the adhesion ofthose cell species being stimulated which should in each case effect thetissue integration of the corresponding biomaterial. Using suchcoatings, an accelerated and enhanced integration of variousbiomaterials/implants with improved long-term stability after theirincorporation into the body can be achieved.

[0022] The peptides according to the invention bind selectively tointegrins. After immobilization on biocompatible surfaces, e.g.implants, they stimulate the adhesion of cells which carry integrins.

[0023] After coating of the compounds on the surfaces, those cellspecies can selectively be stimulated to binding which should alsoeffect the implant integration after implantation in the natural tissue.In osteoblasts, osteoclasts and endothelial cells these are, forexample, α_(v)-carrying cell species.

[0024] The invention therefore relates to the compounds of the formula Ias integrin inhibitors for selective cell enrichment in implants.

[0025] After anchoring to a biocompatible surface as pharmaceuticalactive compounds, the compounds of the formula I can be employed inhuman and veterinary medicine, in particular they can be employed asintegrin inhibitors for the treatment of disorders, defects andinflammations caused by implants, such as inadequate and delayedintegration of biomaterials and implants, of thrombosis caused byimplants, of bone and tooth defects, and of osteolytic disorders such asosteoporosis, thrombosis, cardiac infarct, arteriosclerosis, in woundhealing for assisting the healing process, and also for the accelerationand strengthening of the integration process of the implant or of thebiocompatible surface into the tissue. The compounds of the formula Ican be employed as substances having antimicrobial action in operationswhere biomaterials, implants, catheters or cardiac pacemakers are used.They have an antiseptic action here. The efficacy of the antimicrobialactivity can be demonstrated by the procedure described by P.Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).

[0026] The invention thus relates to the compounds of the formula I asintegrin inhibitors for the treatment of disorders, defects andinflammations caused by implants, and of osteolytic disorders such asosteoporosis, thrombosis, cardiac infarct and arteriosclerosis, and alsofor the acceleration and strengthening of the integration process of theimplant or of the biocompatible surface into the tissue.

[0027] The invention further relates to the use of compounds of theformula I for the production of a medicament for the treatment ofdisorders, defects and inflammations caused by implants, and ofosteolytic disorders such as osteoporosis, thrombosis, cardiac infarctand arteriosclerosis, and for the acceleration and strengthening of theintegration process of the implant or of the biocompatible surface intothe tissue.

[0028] Corresponding peptides carrying phosphonate anchors can be bondedionically to carriers with oxide-containing surfaces, such as implants,affinity chromatography materials, or microtitre plates or else tocation-containing surfaces such as on amorphous or sintered calciumphosphates (e.g. hydroxyapatite, bones, teeth) or calcium phosphatecements (e.g. Biocement D).

[0029] The invention also relates to the use of compounds of the formulaI for the coating, by means of ionic or adsorptive binding, of implantsfor human and animal organs.

[0030] The abbreviations of amino acid residues mentioned above andbelow stand for the radicals of the following amino acids: Abu4-aminobutyric acid Aha 6-aminohexanoic acid, 6-aminocaproic acid Alaalanine Asn asparagine Asp aspartic acid Arg arginine Cys cysteine Dab2,4-diaminobutyric acid Dap 2,3-diaminopropionic acid Gln glutamine Glppyroglutamic acid Glu glutamic acid Gly glycine His histidine homo-Phehomo-phenylalanine Ile isoleucine Leu leucine Lys lysine Met methionineNle norleucine Orn ornithine Phe phenylalanine Phg phenylglycine4-Hal-Phe 4-halophenylalanine Pro proline Ser serine Thr threonine Trptryptophan Tyr tyrosine Val valine.

[0031] In addition, the abbreviations below have the meanings: Ac acetylBOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCIdicyclohexylcarbodiimide DMF dimethylformamide EDCIN-ethyl-N,N′-(dimethylaminopropyl)carbodi- imide Et ethyl FCAfluoresceincarboxylic acid FITC fluorescein isothiocyanate Fmoc9-fluorenylmethoxycarbonyl FTH fluoresceinthiourea HOBt1-hydroxybenzotriazole Me methyl MBHA 4-methylbenzhydrylamine Mtr4-methoxy-2,3,6-trimethylphenylsulfonyl HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HONSu N-hydroxysuccinimide OtBu tert-butyl ester Octoctanoyl OMe methyl ester OEt ethyl ester POA phenoxyacetyl Pbfpentamethylbenzofuranyl Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Salsalicyloyl Su succinyl TIPS triisopropylsilane TFA trifluoroacetic acidTMSBr trimethylsilyl bromide Trt trityl (triphenylmethyl).

[0032] If the abovementioned amino acids can occur in a number ofenantiomeric forms, all these forms and their mixtures (e.g. the DLforms) are included above and below, e.g. as part of the compounds ofthe formula I. In addition, the amino acids, e.g. as part of compoundsof the formula I, can be provided with corresponding protective groupswhich are known per se. Above all, side chain modifications of arginine,such as were carried out, for example, in the case of the non-peptideα_(v)β₃ antagonists (e.g. by R. Keenan et al., Abstr. Pap. 211th ACSNational Meeting (New Orleans, USA) 1996, MEDI 236), can also beemployed in the case of the cyclopeptides, e.g. benzimidazolederivatives instead of the guanidine group.

[0033] “Prodrug derivatives” are also included in the compoundsaccording to the invention, i.e. compounds of the formula I modifiedwith, for example, alkyl or acyl groups, sugars or oligopeptides, whichare rapidly cleaved in the body to give the active compounds accordingto the invention.

[0034] The invention further relates to an implant which is suitable forhuman and animal organs, consisting of a carrier matrix and a layer of abioactive, cell adhesion-mediating molecule surrounding this matrix, thesurrounding layer being formed from a compound of the formula I, and anionic or adsorptive bond being present between carrier matrix and thiscompound. Preferably, the carrier matrix and/or its surface consists ofa metal or metal oxide. Particularly preferably, the carrier matrixand/or its surface consists of a bone or tooth substitute material, e.g.of calcium phosphate mixtures.

[0035] The invention further relates to a process for the preparation ofcompounds of the formula I according to claim 1, and of their salts,characterized in that a bioactive molecule B, which can be provided withprotective groups, and a spacer-anchor molecule (Q-X₁) or anchormolecule (X₁) provided with protective groups are linked to one anotherin peptide fashion and the protective groups are then removed, and/or inthat a basic or acidic compound of the formula 1 [sic] is converted intoone of its salts by treating with an acid or base.

[0036] Above and below, the radicals B, Q and X₁ have the meaningindicated under the formula I, if not expressly stated otherwise.

[0037] B is preferably a cyclo-(Arg-Gly-Asp-Z₁)-,

[0038] Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys-,

[0039] Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys-,

[0040] Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys-,

[0041] Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-,

[0042] Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn- or a

[0043] Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg- residue,

[0044] where Z₁ is, in each case independently of one another, an aminoacid residue or a di- or tripeptide residue, where the amino acids areselected, independently of one another, from the group consisting ofAla, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Homo-Phe, Ile, Leu, Lys,Orn, Met, Phe, Phg, Pro, Ser, Thr, Trp, Tyr, Val.

[0045] Q is absent or is an organic spacer molecule. Preferably, this isa [CO—(CH₂)_(x)—NH]_(m), [CO—CH₂(O—CH₂CH₂)_(y)—NH—]_(m)—,[CO—(CH₂)_(z)—CO]—, [NH—(CH₂)_(z)—NH—]—,[CO—CH₂—(OCH₂CH₂)_(y)—O—CH₂—CO—]— or an [NH—CH₂CH₂—(OCH₂CH₂)_(y)—NH—]—radical, and their combinations, where the ranges of values claimed inclaim 3 apply to the indices m, x, y and z. The abovementioned compoundswhich can assume values between 1 and 8 for m, values between 1 and 5for x and values between 1 and 6 for y and z have proved particularlyadvantageous.

[0046] X₁ is an anchor molecule, preferably from the group-Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂, -Lys-[Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂ or-Lys-(Lys[-Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂)₂, where n can in caseindependently of one another be 0, 1, 2, or 3.

[0047] The amino acids and amino acid residues mentioned in the meaningsfor Z₁ may also be derivatized, with N-methyl, N-ethyl, N-propyl,N-benzyl or Ca-methyl derivatives being preferred. Also preferred arederivatives of Asp and Glu, especially the methyl, ethyl, propyl, butyl,tert-butyl, neopentyl or benzyl esters of the side-chain carboxylgroups, as well as derivatives of Arg, which may be substituted on the—NH—C(═NH)—NH₂ group by an acetyl, benzoyl, methoxy-carbonyl orethoxycarbonyl radical.

[0048] X is preferably H₂N—C(═NH)—NH—, Het-NH—, H₂N—C(═NH)—, A-C(═NH)—NHor a Het radical. (CH₂) S(CH₂)₁

[0049] Y is preferably —(CH₂)_(n)— or

[0050] —(CH₂)_(s)—CH(R⁴) —(CH₂)_(t)— or —(CH₂)_(p)-Het¹-(CH₂)_(q)—radical.

[0051] Z is preferably N—R² or CH—R², where R² can preferably be an Hatom or alkyl radical having 1 to 4 C atoms.

[0052] R³ is preferably an H atom, Ar, Het or A radical, where A, Ar andHet have one of the meanings indicated previously or below.

[0053] R⁴ is preferably an H atom, A, Ar, OH, OA, OAr, arylalkyl, Hal,CN, NO₂ CF₃ or OCF₃ radical. Arylalkyl is preferably benzyl,phenylethyl, phenylpropyl or naphthylmethyl, particularly preferablybenzyl.

[0054] A is preferably a COOH, NH₂ or alkyl radical having 1 to 6 Catoms, which is unsubstituted or substituted by COOH or NH₂. A ispreferably methyl, furthermore ethyl, propyl, n-butyl, isobutyl,sec-butyl or tert-butyl, in addition also n-pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. A isparticularly preferably methyl.

[0055] Ar is preferably phenyl which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, CF₃, OCF₃, CN, NO₂ or Hal, which can besubstituted by phenyl which is mono-, di- or trisubstituted by A, OH,OA, NH₂, OCF₃, CN, NO₂ or Hal in such a way that an unsubstituted orsubstituted biphenyl results.

[0056] Ar is therefore preferably phenyl, o-, m- or p-methyl-phenyl, o-,m- or p-ethylphenyl, o-, m- or p-propyl-phenyl, o-, m- orp-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,o-, m-, p-trifluoromethylphenyl, o-, m-, p-trifluoromethoxy-phenyl, o-,m- or p-fluorophenyl, o-, m- or p-chloro-phenyl, o-, m- orp-bromophenyl, o-, m-. p-nitrophenyl, o-, m- or p-aminomethylphenyl.

[0057] Het is a saturated, partly or completely unsaturated mono- orbicyclic heterocyclic radical having 5 to 10 ring members, where 1 to 3N and/or 1 S or O atom(s) can be present and the heterocyclic radicalcan be mono- or disubstituted by CN, Hal, OH, NH₂, COOH, OA, CF₃, A,NO₂, Ar or OCF₃. Het is preferably an o-, m- or p-substituted pyridyl, a2-, 4-, 5- or 6-substituted pyrimidyl or a 3-, 4-, 5- or 6-substitutedpyridazyl which is preferably unsubstituted or substituted by a methyl,ethyl or propyl group or a methylamino, ethylamino or propylamino group[relates to all of the three heteroaromatics mentioned], and also a2-substituted benzimidazolyl which is unsubstituted or substituted by a3-methyl, 3-ethyl or 3-benzyl group, and also a 2-substituteddihydroimidazolyl, tetrahydropyrimidyl or tetrahydro-pyridyl.

[0058] Examples which are preferably contained in Het are:

[0059] Het₁ is a 5- or 6-membered aromatic heterocycle having 1 to 4 N,O and/or S atoms, which can be unsubstituted or mono- or disubstitutedby F, Cl, Br, A, OA or OCF₃.

[0060] Het¹ is preferably a 2,4-, 3,5- or 2,5-disubstituted pyridyl or a2,4-, 2,5-, 2,6- or 4,6-disubstituted pyrimidyl, a 2,4- or2,5-disubstituted 1,3-oxazolyl or 1,3-thiazolyl.

[0061] OA is preferably methoxy, ethoxy, propoxy or butoxy, in additionalso pentyloxy or hexyloxy.

[0062] Hal is preferably F, Cl or Br, but also I.

[0063] The indices n, m, o, p, q, s and t have the meaning indicated inclaim 2, if not expressly stated otherwise.

[0064] The compounds of the formula I can have one or more chiralcentres and therefore occur in various stereo-isomeric forms. Theformula I includes all these forms.

[0065] Accordingly, the invention relates in particular to thosecompounds of the formula I in which at least one of the radicalsmentioned has one of the preferred meanings indicated above.

[0066] Particularly preferred compounds of the formula I are thefollowing:

[0067] a)Cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)H—[CO—(CH₂)₅—NH]₂-Lys-[Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂));

[0068] b) Cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)H—[CO—(CH₂)₅—NH]₃-Lys-[Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂));

[0069] c) Cyclo-(Arg-Gly-Asp-D-Phe-Lys —(N^(ε)H-[CO—CH₂(—O—CH₂CH₂)₆—NH]₂-Lys-[Lys-(CO—CH₂—(CH₂) —PO₃H₂)₂]₂));

[0070] where n is 1.

[0071] The compounds of the formula I and also the starting substancesfor their preparation are otherwise prepared by methods known per se,such as are described in the literature (e.g. in the standard works suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart;) namely under reactionconditions which are known and suitable for the reactions mentioned. Usecan also be made in this case of variants which are known per se, butnot mentioned here in greater detail.

[0072] If desired, the starting substances can also be formed in situsuch that they are not isolated from the reaction mixture, butimmediately reacted further to give the compounds of the formula I.

[0073] The fragment coupling or the coupling between ligand and linkeris generally carried out in an inert solvent, a carboxylic acid fragment(phosphonate linker, e.g.HO—[CO—(CH₂)₅—NH]₂-Lys-[Lys-(CO—CH₂—CH₂—PO₃(C₂H₅)₂)₂]₂) being dissolvedin DMF with HATU, HOAt and 2,4,6-collidine and treated with an aminefragment (cyclopeptide, e.g. c[R(Pbf)G(OtBu)fK]).

[0074] Suitable inert solvents are, for example, hydrocarbons such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, chloroform or dichloromethane; alcohols such as methanol,ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl or monoethyl ether(methyl glycol or ethyl glycol), ethylene glycol dimethyl ether(diglyme); ketones such as acetone or butanone; amides such asacetamide, N-methylpyrrolidone, dimethylacetamide or dimethylformamide(DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO), carbon disulfide; carboxylic acids such as formic acidor acetic acid; nitro compounds such as nitromethane or nitrobenzene;esters such as ethyl acetate, water or mixtures of the solventsmentioned.

[0075] Cyclic compounds can be prepared by cyclization of the linearcompounds, such as described, for example, in DE 43 10 643, inHouben-Weyl, l.c., Volume 15/II, pages 1 to 806 (1974) or by S. Zimmer,E. Hoffmann, G. Jung and H. Kessler, Liebig's Ann. Chem. 1993, 497-501.

[0076] The linear peptides can be synthesized, for example, according toR. B. Merrifield, Angew. Chemie 1985, 97, 801-812.

[0077] Open-chain linear compounds, such as, for example, compounds ofthe formula I can otherwise be prepared by customary methods of aminoacid and peptide synthesis, e.g. also by the solid-phase synthesisaccording to Merrifield (see also, for example, B. F. Gysin and R. B.Merrifield, J. Am. Chem. Soc. 94, 3012 ff. (1972)).

[0078] The compounds of the formula I can furthermore be obtained byliberating them from their functional derivatives by solvolysis, inparticular hydrolysis, or by hydrogenolysis.

[0079] Preferred starting substances for the solvolysis orhydrogenolysis are those which, instead of one or more free amino and/orhydroxyl groups, contain corresponding protected amino and/or hydroxylgroups, preferably those, which instead of an H atom which is bonded toan N atom, carry an amino protective group, e.g. those which correspondto the formula I, but instead of an NH₂ group contain an NHR′ group (inwhich R′ is an amino protective group, e.g. BOC or CBZ).

[0080] Starting substances are furthermore preferred which, instead ofthe H atom of a hydroxyl group, carry a hydroxyl protective group, e.g.those which correspond to the formula I, but instead of a hydroxyphenylgroup contain an R″O— phenyl group (in which R″ is a hydroxyl protectivegroup).

[0081] A number of —identical or different—protected amino and/orhydroxyl groups can also be present in the molecule of the startingsubstance. If the protective groups present are different from oneanother, in many cases they can be removed selectively.

[0082] The expression “amino protective group” is generally known andrelates to groups which are suitable for protecting (for blocking) anamino group from chemical reactions, but which are easily removableafter the desired chemical reaction has been carried out at otherpositions in the molecule. Typical groups of this type are, inparticular, unsubstituted or substituted acyl, aryl, aralkoxymethyl oraralkyl groups. Since the protective groups are removed after thedesired reaction (or reaction sequence), their nature and size isotherwise uncritical; preferably, however, those having 1-20, inparticular 1-8, C atoms are preferred. The expression “acyl group” is tobe interpreted in the widest sense in connection with the presentprocess. It includes acyl groups derived from aliphatic, araliphatic,aromatic or heterocyclic carboxylic acids or sulfonic acids and also, inparticular, alkoxycarbonyl, aryloxycarbonyl and especiallyaralkoxycarbonyl groups. Examples of acyl groups of this type arealkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such asphenylacetyl; aroyl such as benzoyl or toluyl; aryloxy-alkanoyl such asPOA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl;aralkyloxycarbonyl such as CBZ (“carbobenzoxy”),4-methoxy-benzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr Pbf or Pmc.Preferred amino protective groups are BOC and Mtr, additionally CBZ,Fmoc, benzyl and acetyl.

[0083] The expression “hydroxyl protective group” is likewise generallyknown and relates to groups which are suitable for protecting a hydroxylgroup from chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out at other positions in themolecule. Typical groups of this type are the abovementionedunsubstituted or substituted aryl, aralkyl or acyl groups andadditionally also alkyl groups. The nature and size of the hydroxylprotective groups is not critical, since they are removed again afterthe desired chemical reaction or reaction sequence; groups containing1-20, in particular 1-10, C atoms are preferred. Examples of hydroxylprotective groups are, inter alia, benzyl, p-nitro-benzyl,p-toluenesulfonyl, tert-butyl and acetyl, benzyl and tert-butyl beingparticularly preferred. The COOH groups in aspartic acid and glutamicacid are preferably protected in the form of their tert-butyl esters(e.g. Asp(OtBu)).

[0084] The liberation of the compounds of the formula I from theirfunctional derivatives is carried out—depending on the protective groupused—, for example using strong acids, expediently using TFA orperchloric acid, but also using other strong inorganic acids such ashydrochloric acid or sulfuric acid, strong organic carboxylic acids suchas trichloroacetic acid or sulfonic acids such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible, but not always necessary. Suitable inert solvents arepreferably organic solvents, for example carboxylic acids such as aceticacid, ethers such as tetrahydrofuran or dioxane, amides such as DMF,halogenated hydrocarbons such as dichloromethane, additionally alsoalcohols such as methanol, ethanol or isopropanol, and also water.Mixtures of the abovementioned solvents are additionally suitable. TFAis preferably used in an excess without addition of a further solvent,perchloric acid in the form of a mixture of acetic acid and 70%perchloric acid in the ratio 9:1. The reaction temperatures for thecleavage are expediently between approximately 0 and approximately 50°,the reaction is preferably carried out between 15 and 30° (roomtemperature). The groups BOC, OtBu and Mtr can be removed, for example,preferably using TFA in dichloromethane or using approximately 3 to 5 NHCl in dioxane at 15-30°, the FMOC group using an approximately 5 to 50%solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.

[0085] The trityl group is employed for the protection of the aminoacids histidine, asparagine, glutamine and cysteine. Removal is carriedout, depending on the desired final product, using TFA/10% thiophenol,the trityl group being removed from all the abovementioned amino acids,when using TFA/anisole, TFA/thioanisole or TFA/TIPS/H₂O the trityl grouponly being removed from His, Asn and. Gln, compared to which that on theCys side chain remains.

[0086] The Pbf (pentamethylbenzofuranyl) group is employed for theprotection of Arg. Removal is carried out, for example, using TFA indichloromethane. Hydrogenolytically removable protective groups (e.g.CBZ or benzyl) can be removed, for example, by treating with hydrogen inthe presence of a catalyst (e.g. of a noble metal catalyst such aspalladium, expediently on a support such as carbon). Suitable solventsin this case are those indicated above, in particular, for example,alcohols such as methanol or ethanol or amides such as DMF. As a rule,the hydrogenolysis is carried out at temperatures between approximately0 and 100° and pressures between approximately 1 and 200 bar, preferablyat 10-30° and 1-10 bar. Hydrogenolysis of the CBZ group is readilycarried out, for example, on 5 to 10% Pd/C in methanol or using ammoniumformate (instead of hydrogen) on Pd/C in methanol/DMF at 10-30°.

[0087] A base of the formula I can be converted into the associated acidaddition salt using an acid, for example by reaction of equivalentamounts of the base and of the acid in an inert solvent such as ethanoland subsequent evaporation. Possible acids for this reaction are inparticular those which give physiologically acceptable salts. Thusinorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalicacids such as hydrochloric acid or hydrobromic acid, phosphoric acidssuch as orthophosphoric acid, sulfamic acid, additionally organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,e.g. formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methane- or ethanesulfonic acid, ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, naphtha- lenemono- and -disulfonic acids, and laurylsulfuric acid.Salts with physiologically unacceptable acids, e.g. picrates, can beused for the isolation and/or purification of the compounds of theformula I.

[0088] On the other hand, an acid of the formula I can be converted intoone of its physiologically acceptable metal or ammonium salts byreaction with a base. Suitable salts in this case are in particular thesodium, potassium, magnesium, calcium and ammonium salts, additionallysubstituted ammonium salts, e.g. the dimethyl-, diethyl- ordiisopropylammonium salts, monoethanol-, diethanol- ordiisopropylammonium salts, cyclohexyl- or dicyclohexylammonium salts,dibenzylethylenediammonium salts, furthermore, for example, salts witharginine or lysine.

[0089] Above and below, all temperatures are indicated in ° C. In thefollowing examples “customary working up” means: if necessary, water isadded, the mixture is adjusted, if necessary, depending on theconstitution of the final product, to a pH of between 2 and 10 andextracted with ethyl acetate or dichloromethane, the organic phase isseparated off, dried over sodium sulfate and evaporated, and the residueis purified by chromatography on silica gel and/or by crystallization.R_(f) values on silica gel: eluent: ethyl acetate/methanol 9:1.

[0090] RT=Retention time (minutes) on HPLC in the following systems: [A]Column: YMC ODS A RP 5C₁₈, 250 × 4.6 mm Eluent A: 0.1% TFA in waterEluent B: 0.1% TFA in acetonitrile Flow rate: 1 ml/min Gradient: 0-50%B/30 min. [B] as [A]; Gradient: 5-50% B/30 min. [C] as [A]; Gradient:10-50% B/30 min.

[0091] Mass Spectrometry (MS):

[0092] EI (electron impact ionization) M⁺

[0093] FAB (Fast Atom Bombardment) (M+H)⁺

[0094] ESI (Electrospray ionization) (M+H)⁺

[0095] DMPP resin stands for4-(2′,4′-dimethoxyphenylhydroxy-methyl)phenoxy resin, which allows, forexample, the synthesis of side chain-protected peptides; TCP resin meanstrityl chloride-polystyrene resin.

[0096] The following examples describe on the one hand the fragmentcoupling and the cleavage of phosphonic esters, and the other hand thesynthesis of selected cyclopeptide derivatives with phosphonate linker.The process for coating the various shaped articles made of metal orbone substitute materials is explained in detail by means of Examples 7to 9.

EXAMPLE 1 Fragment Coupling in Solution

[0097] 0.2 mmol of carboxylic acid fragment (phosphonate linker, e.g.HO—[CO—(CH₂)₅—NH]₂-Lys-[Lys-(CO—CH₂—CH₂—PO₃(C₂H₅)₂)₂]₂), 0.98 eq ofHATU, 1.1 eq of HOAt and 10 eq of 2,4,6-collidine are dissolved in 2 mlof DMF. After 1.5 h, 1 eq of amine fragment (cyclopeptide, e.g.c[R(Pbf)G(OtBu)fK]) is added. The mixture is left to stir at roomtemperature for 24 h, and the product is purified by preparative HPLC.

EXAMPLE 2 Cleavage of Phosphonic Esters at the Phosphonate Linkers

[0098] The peptide with phosphonic ester groups is dissolved or, whereapropriate, suspended in an ultrasonic bath in a 10:1 mixture of abs.CHCl₃ and TMSBr. After stirring for 3 days and, where appropriate,occasional slurrying of the precipitate in an ultrasound bath, thesolvent is distilled off. The residue is lyophilized from H₂O.

[0099] The acidic side-chain protective groups are removed byconventional techniques.

EXAMPLE 3 Synthesis of the Phosphonate Linkers

[0100] The phosphonate linkers were synthesized in a solid-phase peptidesynthesis according to the Fmoc strategy (see G. B. Fields, R. L. Nobie,Int. J. Pept. Protein Res. 1990, 35, 161-214).

[0101] The last building block coupled was 3-diethylphosphono-propionicacid.

[0102] Synthesis of 3-diethylphosphonopropionic Acid:

[0103] Benzyl 3-bromopropionate

[0104] 58.3 mmol of 3-bromopropionyl chloride (10.0 g) and 1 eq ofbenzyl alcohol (6.3 g) are dissolved in 100 ml of dry DCM with stirringin a 250 ml round-bottomed flask with calcium chloride tube. After 2days, 200 ml of CHCl₃ are added to the mixture, and the organic phase isextracted twice with saturated NaHCO₃ solution. After drying over MgSO₄,the solvent is distilled off, and the product is obtained as acolourless liquid.

[0105] Yield: 13.8 g (56.8 mmol, 97%) R_(f)=0.75 (H:EA 1:1).

[0106] NMR (CDCl₃):

[0107]¹H (250 MHz): δ=7.35 (s, 5H; H ar), 5.16 (s, 2H; CH₂—OCO), 3.58(t, ³J(H,H)=7 Hz, 2H; CH₂Br), 2.95 (t, ³J(H,H)=7 Hz, 2H; CH₂CO).

[0108] GC-MS: r+=242.0.

[0109] Benzyl 3-diethylphosphonopropionate

[0110] 56.8 mmol of benzyl 3-bromopropionate (13.8 g) and 1.7 eq oftriethyl phosphite (16.0 g) are heated to 140° C. with stirring in adistillation apparatus sealed with a gas balloon for pressureequalization. The bromoethane formed during the reaction is distilledout continuously and collected in a receiver flask cooled to 0° C. After4 h, the remaining oily residue is fractionally distilled under highvacuum through a Vigreux column; the product is a colourless oil.

[0111] Yield: 12.1 g (40.3 mmol, 71%), slightly impure, R_(f)=0.33 (A:H2:3)

[0112] For greater purity, the product can be purified where appropriateby flash chromatography (eluent A:H 2:3).

[0113] NMR (CDCl₃):

[0114]¹H (250 MHz): δ=7.31 (s, 5H; H ar), 5.10 (s, 2H, CH₂—OCO), 4.05(m, 4H; CH₂OP), 2.61 (m, 2H; CH₂CO), 2.04 (m, 2H; CH₂P), 1.26 (t,³J(H,H)=7 Hz, 6H; CH₃).

[0115]³¹P (101.256 MHz): δ=28.5 (s)

[0116] GC-MS: m+=300.0.

[0117]3-Diethylphosphonopropionic Acid

[0118] 40.3 mmol of benzyl 3-diethylphosphonopropionate (12.1 g) aredissolved in 100 ml of ethanol, and 2 g of catalyst (5% Pd/C) are added.After stirring under an H₂ atmosphere for 4 h, the active carbon isfiltered off, and the solvent is distilled out. The product results as acolourless oil which slowly solidifies to a colourless solid at roomtemperature. The product is slightly contaminated with ethyl3-diethylphosphono-propionate which, where appropriate, can betransferred into the organic phase by shaking several times with waterand hexane, and be removed.

[0119] Yield: 8.2 g (39.0 mmol, 97%).

[0120] NMR (CDCl₃):

[0121]¹H (250 MHz): S=10.60 (bs, 1H; COOH), 4.07 (m, 4H; CH₂O), 2.59 (m,2H; CH₂CO), 2.06 (m, 2H; CH₂P), 1.29 (t, ³J(H,H)=7 Hz, 6H; CH₃)

[0122]¹³C (62.896 MHz): δ=174.5 (d, J(C,P)=18.5 Hz; COOH), 62.1 (d,J(C,P)=6.6 Hz; CH₂—O), 27.1 (d, J(C,P)=3.8 Hz; CH₂—COOH), 2.07 (d,J(C,P)=144.9 Hz; CH₂—P), 16.2 (d, J(C,P)=6.1 Hz; CH₃).

[0123]³¹P (101.256 MHz): δ=29.5 (s).

[0124] Analytical Data for the Cyclopeptides with Phosphonate Linker

EXAMPLE 4 2 Aminohexanoic Acids in the Spacer

[0125] Cyclo-(Arg-Gly-Asp-DPhe-Lys(N(—[CO—(CH₂)₅—NH]₂-Lys-[Lys-(CO—CH₂—CH₂—PO₃H₂)₂]₂))

[0126] MS (ESI): m/z (%): 1756.9 (100) [m−H⁺], 1778.8 (48) [m+Na⁺−2H⁺],1794.9 (18) [m+K⁺−2H⁺].

[0127] NMR ([D₆]DMSO):

[0128]³¹p (101.256 MHz): δ=29.63 (s, 1P), 29.59 (s, 1P) 29.57 (s, 1P),29.38 (s, 1P).

EXAMPLE 5 3 Aminohexanoic Acids in the Spacer

[0129] Cyclo-(Arg-Gly-Asp-DPhe-Lys(N^(ε)H—[CO—(CH₂)₅—NH]₃-Lys-[Lys-(CO—CH₂—CH₂—PO₃H₂)₂]₂)

[0130] MS (ESI): m/z (%): 934.9 (100) [m−2H⁺], 1870.0 (27) [m−H⁺].

[0131] NMR ([D₆]DMSO):

[0132]³¹p (101.256 MHz): δ=29.57 (s, 1P), 29.51 (s, 2P), 29.33 (s, 1P).

EXAMPLE 6 2 Heptaethylene Glycol Amino Carboxylic Acids in the Spacer

[0133] Cyclo-(Arg-Gly-Asp-DPhe-Lys(NH—[CO—CH₂(—O—CH₂CH₂)₆—NH]₂-Lys-[Lys-(CO—CH₂—CH₂—PO₃H₂)₂]₂))

[0134] MS (ESI): m/z (%): 1086.4 (100) [m−2H⁺], 1097.7 (73) [m+Na⁺−3H⁺]

[0135] NMR ([D₆]DMSO):

[0136]³¹p (101.256 MHz): δ=29.66 (s, 1P), 29.61 (s, 1P), 29.59 (s, 1P),29.45 (s, 1P).

[0137] In addition, all the aforementioned peptides were characterizedby ¹H NMR spectroscopy (250 MHz), and the expected spectra wereobtained.

EXAMPLE 7

[0138] Ti or TiAl₆V₄ shaped articles with a diameter of 10 mm and aheight of 1-2 mm are precleaned in distilled water at 60° C. in anultrasonic bath for 15 min, then washed with acetone for 30 min and thentwice with distilled water, and dried in a drying oven for eight hours.

[0139] The shaped articles are transferred into 48 wells (Costar,“non-tissue culture treated” Art. No. 3574). To attach the bioactive,cell adhesion-mediating molecules B (where B can be a cyclopeptide,peptide mimetic or linear peptide according to claim 2) to the preparedshaped articles, molecule B-containing stock solutions (“B solutions”)are prepared in a final concentration of 1 mM in one of the aqueousbuffers Tris-HCl (10 mM, pH 8.7), Tris-HClO₄ (10 mM, pH 8.7) or PBS, pH7.4. Concentration series with the “B solutions” final concentrations ofin each case 1 nm, 10 nm, 100 nm, 1 μm, 10 Am and 100 μm are thenprepared by dilution with PBS, pH 7.4. The shaped articles are eachcovered with 250 Al of the respective B solution and then incubated atroom temperature for 18-24 hours. To remove unbound B molecules, thesamples are washed three times with PBS, pH 7.4, and stored in PBS, pH7.4, at 4° C. overnight.

[0140] Nonspecific cell binding sites are blocked by adding 250 μl of a5% BSA (bovine serum albumine) solution, pH 7.4, to each shaped article,then incubating at room temperature for 2 hours and washing once withPBS, pH 7.4.

[0141] Ti and TiAl₆V₄ shaped articles which are treated withcorresponding buffer solutions (Tris-HCl 10 mM, pH 8.7; Tris-HClO₄ 10mM, pH 8.7; PBS, pH 7.4) instead of B solutions serve as negativecontrols.

[0142] The extent of the resulting coatings on the shaped articles isassessed by analysis, and the biological activity is determined in vitroby means of a cell adhesion test.

EXAMPLE 8

[0143] Ivory shaped articles as model of a natural bone substitutematerial with a diameter of 10 mm and a height of 100 μm-are produced bycutting out cylinders with a diameter of 10 mm and subsequently sawingto a thickness of 100 μm in a Buehler ISOMET low speed saw. The samplesare then cleaned in distilled water at 60° C. in an ultrasonic bath for10 min and thereafter washed twice with distilled water and dried in adrying oven for 8 hours.

[0144] The procedure for coating the shaped articles with B solutions isas described in example 7.

[0145] The extent of the resulting coating on the shaped articles isassessed by analysis, and the biological activity is determined in vitroby means of a cell adhesion test.

EXAMPLE 9

[0146] Shaped articles of the commercially available bone substitutematerial Endobon® (from Biomet Merck, Germany) with a diameter of 10 mmand a height of 100 μm are produced by cutting out cylinders with adiameter of 10 mm and subsequently sawing to a thickness of 100 μm in aBuehler ISOMET low speed saw. The samples are then cleaned in distilledwater at 60° C. in an ultrasonic bath for 10 min and thereafter washedtwice with distilled water and dried in a drying oven for 8 hours.

[0147] The procedure for coating the shaped articles with B solutions isas described in example 7.

[0148] The extent of the resulting coating on the shaped articles isassessed by analysis, and the biological activity is determined in vitroby means of a cell adhesion test.

[0149] Example for Cell Adhesion Test

[0150] The adhesion of mouse MC3T3 H1 osteoblast cultures in vitro toRGD-peptide-coated material surfaces was investigated. In this test, 50000 cells/cm² were inoculated and, after incubation in serum-free mediumat 37° C./95% atmospheric humidity for one hour, the proportion ofadhered cells was determined.

[0151] Cell adhesion rate [%]=adhered cells/inoculated cells×100

[0152] Peptide: cell adhesion rate [%]

[0153] Cyclo-(Arg-Gly-Asp-DPhe-Lys(DH-[CO—(CH₂)₅—NH]₂-Lys-[Lys-(CO—CH₂—CH₂—PO₃H₂)₂]₂): 75

[0154] Cyclo-(Arg-Gly-Asp-DPhe-Lys((H-[CO—(CH₂)₅—NH]₃-Lys-[Lys-(CO—CH₂—CH₂—PO₃H₂)₂]₂)): 62

1. Compound of the formula I B-Q-XL  1 in which B is a bioactive, celladhesion-mediating molecule, Q is absent or is an organic spacermolecule and X₁ is an anchor molecule, selected from the group-Lys-(CO—CH₂—(CH₂) —PO₃H₂)₂ (i) -Lys-[Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂(ii) or -Lys-(Lys[-Lys-(CO—CH₂—(CH₂)_(n)-PO₃H₂)₂]₂ (iii), and n, in eachcase independently of one another, is 0, l 2 or 3 and a free amino groupof the group B and a free carboxyl group of the spacer molecule Q or ofthe anchor molecule XI or a free amino group of the radical Q and a freecarboxyl group of the radical X₁ are linked to one another likepeptides, and its salts.
 2. Compound according to claim 1, in whichgroup B is selected from the group cyclo-(Arg-Gly-Asp-Z₁) (iv)

and Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys (vi)Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys (vii)Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys (viii)Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg (ix)Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn (x)Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg (xi) where Z₁ is, in each caseindependently of one another, an amino acid residue or a di- ortripeptide residue, where the amino acids are selected, independently ofone another, from a group consisting of Ala, Asn, Asp, Arg, Cys, Gln,Glu, Gly, His, Homo-Phe, Ile, Leu, Lys, Met, Orn, Phe, Phg, Pro, Ser,Thr, Trp, Tyr, Val, where for (v) x is H₂N—C(═NH)—NH, Het-NH—,H₂N—C(═NH)—, A-C(═NH)—NH— or Het-, Y is —(CH₂)_(n)— or

 —(CH₂)_(s)—CH(R⁴)—(CH₂)_(t)— or —(CH₂)_(p)-Het¹-(CH₂)_(q)—, Z is N—R²or CH—R², R² is H or alkyl having 1 to 4 C atoms, R³ is H, Ar, Het or A,R⁴ is H, A, Ar, OH, OA, OAr, arylalkyl, Hal, CN, NO₂, CF₃ or OCF₃, A isCOOH, NH₂ or alkyl having 1-6 C atoms, unsubstituted or substituted byCOOH or NH₂, Ar is phenyl which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, CF₃, OCF₃₁ CN, NO₂ or Hal, which can besubstituted by a phenyl which is mono-, di- or trisubstituted by A, OH,OA, NH₂, OCF₃, CN, NO₂ or Hal in such a way that an unsubstituted orsubstituted biphenyl results, Hal is F, Cl, Br or I, Het is a saturated,partly or completely unsaturated mono- or bicyclic heterocyclic radicalhaving 5 to 10 ring members, where 1 to 3 N and/or 1 S or O atom(s) canbe present and the heterocyclic radical can be mono- or disubstituted byCN, Hal, OH, NH₂, COOH, OA, CF₃, A, NO₂, Ar or OCF₃, Het₁ is a 5- or6-membered aromatic heterocycle having 1 to 4 N and/or S atoms, whichcan be unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA orOCF₃, n is 4, 5 or 6, m, o, p, q are 0, 1 or 2, s, t are 0, 1, 2, 3, 4or 5
 3. Compound according to claim 1 or 2, in which Q is selected fromthe group [CO—(CH₂)_(x)NH]_(m), (xii) [CO—CH₂(—O—CH₂CH₂)_(y)NH]_(m)(xiii) [CO—(CH₂)_(z)—CO—](xiv) [NH—(CH₂)_(z)—NH—](xv)[CO—CH₂—(OCH₂CH₂)_(y)—O—CH₂—CO—](xvi)[NH—CH₂CH₂—(OCH₂CH₂)_(y)—NH—](xvii) and their combination in which m ineach case independently of one another is 1-20, x is 1-12, y is 1-50 andz is 1-12.
 4. Compound according to claim 1 or 2, in which Q is selectedfrom the group [CO—(CH₂)_(x),NH]_(m), (xviii)[CO—CH₂(OCH₂CH₂)_(y)NH]_(m) (xix) [CO—(CH₂)_(z)—CO—](xx)[NH—(CH₂)_(z)—NH—](xxi) [CO—CH₂—(OCH₂CH₂)_(y)—O—CH₂—CO—](xxii)[NH—CH₂CH₂—(OCH₂CH₂)_(y)—NH—](xxiii) and their combination in which m ineach case independently of one another is 1 to 8, x is 1-5, y is 1-6 andz is 1-6.
 5. Compounds of the formula 1 [sic] according to claim 1 a)Cyclo-(Arg-Gly-Asp-DPhe-Lys(N^(ε)H—[CO—(CH₂)₅—NH]₂-Lys-[Lys-(CO—CH₂—(CH₂) —PO₃H₂)₂]₂)); b)Cyclo-(Arg-Gly-Asp-DPhe-Lys(N^(ε)H—[CO—(CH₂)₅—NH]₃-Lys-[Lys-(CO—CH₂—(CH₂) —PO₃H₂)₂]₂)); c)Cyclo-(Arg-Gly-Asp-DPhe-Lys(N^(ε)H—[CO—CH₂(—O—CH₂CH₂)₆—NH]₂-Lys-[Lys-(CO—CH₂—(CH₂)_(n)—PO₃H₂)₂]₂));where n is
 1. 6. Compound according to one of claims 1 to 5 as amedicament for the treatment of disorders, defects and inflammationscaused by implants, and of osteolytic disorders such as osteoporosis,thrombosis, cardiac infarct and arteriosclerosis, and also for theacceleration and strengthening of the integration process of the implantor of the biocompatible surface into the tissue.
 7. Implant, suitablefor human and animal organs, consisting of a carrier matrix and a layerof a bioactive, cell adhesion-mediating molecule surrounding thismatrix, characterized in that the surrounding layer is formed from acompound according to claims 1 to 5, an ionic or adsorptive bond beingpresent between carrier matrix and this compound.
 8. Implant accordingto claim 7, characterized in that the carrier matrix and/or its surfaceis a metal or a metal oxide.
 9. Implant according to claim 7,characterized in that the carrier matrix and/or its surface is a bone ortooth substitute material.
 10. Implant according to claim 9,characterized in that the bone or tooth substitute material consists ofcalcium phosphate mixtures.
 11. Process for the preparation of acompound according to claim 1, and of its salts, characterized in that abioactive molecule B which can be provided with protective groups, and aspacer-anchor molecule (Q-X₁) or anchor molecule (X₁) provided withprotective groups are linked to one another in peptide fashion and theprotective groups are then removed, and/or in that a basic or acidiccompound of the formula I is converted into one of its salts by treatingwith an acid or base.
 12. Use of a compound according to one of claims 1to 5 for the production of a medicament for the treatment of disorders,defects and inflammations caused by implants, and of osteolyticdisorders such as osteoporosis, thrombosis, cardiac infarct andarteriosclerosis, and for the acceleration and strengthening of theintegration process of the implant or of the biocompatible surface intothe tissue.
 13. Use of a compound according to one of claims 1 to 5 forthe coating, by means of ionic or adsorptive binding, of implants forhuman and animal organs.